The Goodpasture antigen is expressed in the human thymus

Abstract

Background. Autoimmunity to kidney antigens causes membranous nephropathy and Goodpasture's disease and very likely is pivotal in many other glomerular diseases. We investigated the potential for central tolerance to the best-characterized kidney autoantigen, the NC1 domain of the α3 chain of type IV collagen [α3(IV)NC1], which is the target of autoimmune attack in Goodpasture's disease. Methods. Indirect immunofluorescence on human thymus and polymerase chain reaction (PCR) and Southern blot analysis of cDNA reverse transcribed from RNA extracted from human thymus and kidney. Results. Indirect immunofluorescence on human thymus demonstrated the presence of α3(IV)NC1 in all six thymus samples examined. The homologous collagen IV chain, α5(IV)NC1, also was detected with a similar intra-thymic distribution. Strikingly, thymic α3 and α5 localized around and within Hassall's corpuscles in the thymic medulla, which are structures implicated in T cell apoptosis and possibly negative selection. In contrast, α1(IV)NC1 localized to the basement membranes of interlobular septa and blood vessels, as is typical of collagen IV chains situated outside the thymus. Reverse transcription-polymerase chain reaction (RT-PCR) confirmed the presence of mRNA encoding α3(IV)NC1 and α5(IV)NC1 in thymic tissue establishing that the antigens were likely to have been synthesized locally. Conclusions. The results demonstrate that α3(IV)NC1 is expressed in the human thymus, and therefore should be available for induction of α3(IV)NC1-specific tolerance. This observation has the important implication that patients' α3(IV)NC1-specific, autoreactive T cells are more likely to recognize cryptic epitopes that are not adequately presented by thymic antigen-presenting cells (APC) than the major antigen-derived epitopes generally identified by conventional approaches.